tbuckley/cabot-search huggingface dataset:
Stimulator of interferon gene (STING) expression as a biomarker for overall survival in PDL1-negative, TMB-low non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs).
Authors: Matthew James Hadfield, Nishant Gandhi, Alex Patrick Farrell, Christopher G. Azzoli, Ari M. Vanderwalde, Balazs Halmos, Stephen V. Liu, Wafik S. El-Deiry, Abdul Rafeh Naqash
Journal: Journal of Clinical Oncology (2023)

9120 Background: cGAS-STING (CGS) is an intracellular DNA sensing pathway that when activated, stimulates interferon and other immune-related signaling pathways. While increased expression of CGS-related genes has been associated with better survival in NSCLC, studies investigating this phenomenon in tumors less likely to respond to ICIs such as PDL1-negative, TMB-Low NSCLC are lacking. Here we report the role of CGS pathway in NSCLC tumors that are both PDL1-negative and TMB-Low. Methods: DNA (592-gene or whole exome) and RNA sequencing (whole transcriptome) was performed for NSCLC specimens (n=7264) submitted to Caris Life Sciences (Phoenix, AZ). PDL1 negativity was defined as &lt;1% TPS score (22C3) &amp; TMB-Low as &lt;10 mutations/Mb. Hierarchical Agglomerative Clustering (HAC) was performed on STING pathway genes (CXCL10, CCL5 and GZB) and tumors were grouped into STING-high (n=3070), STING-intermediate (n=1609) and STING-low (n=2585) groups. Microenvironmental cell populations (MCP)-counter analysis was used to estimate cellular composition of immune cells. Statistical significance was determined using chi-square/Fisher’s exact/Mann-Whitney U tests and adjusted for multiple comparisons (q&lt;0.05). Kaplan Meier method was used to estimate the overall survival (OS) derived from insurance claims of IO treated pts with NSCLC (n=400). Pts were stratified into groups above or below the median expression of the STING gene ( TMEM173). Results: Compared to STING-low, tumors that were STING-high had enrichment in immune cell infiltrates including CD8+ T cells (4.4-fold) and B-cells (5.9-fold); Additionally, STING-high cohort had significantly higher expression of immune checkpoint (IC) genes including CD274(2.5-fold), CD80 (2.7-fold, all q&lt;0.05). STING-high tumors also had a higher prevalence of TP53 mutations (mts) and a lower prevalence of STK11 and KEAP1 mts (Table). Median overall survival (OS) was 21.1 months in the STING-high cohort (n=200) vs 11.9 months in the STING-low cohort (n=199) in IO treated pts (HR = 0.62, p&lt;0.000.1) Conclusions: To our knowledge this is the largest real-world dataset indicating that enrichment of both the STING gene, and gene signatures associated with the STING pathway represent valuable transcriptomic biomarkers to stratify pts with PDL1-negative and TMB-Low NSCLC who benefit more from IO therapies. Conversely, novel IO combination strategies need to be employed in STING-low tumors to enhance outcomes. [Table: see text]
Risk stratification of pancreatic ductal adenocarcinoma patients undergoing curative-intent surgery after neoadjuvant therapy.
Authors: Hyun Kyung Yang, Mi-Suk Park, Kyunghwa Han, Geonsik Eom
Journal: Journal of Clinical Oncology (2023)

e16312 Background: To identify preoperative factors associated with survival in pancreatic ductal adenocarcinoma (PDAC) patients who underwent curative-intent surgery after neoadjuvant therapy (NAT) and develop risk stratification criteria. Methods: Consecutive PDAC patients who underwent post-NAT curative-intent surgeries between 2007 and 2020 at a high-volume center were retrospectively analyzed. Demographic, laboratory, surgical, and histopathologic variables were collected. Baseline, preoperative, and interval changes of CT findings proposed by the Society of Abdominal Radiology and the American Pancreatic Association were analyzed. Cox proportional hazard analyses were used to identify preoperative variables associated with survival since the time of diagnosis. We developed risk stratification criteria using the variables independently associated with survival, i.e., "post-NAT response criteria." We compared the discrimination performance of "post-NAT response criteria" with that of post-NAT pathological (yp) AJCC TNM staging system. Results: A total 145 PDAC patients who completed chemo- (n=47) or chemoradiation therapy (n=98) were included. Stable or increased tumor size on CT (hazard ratio, 2.58 [1.58, 4.21]; P &lt; 0.001) and elevated preop. CA 19-9 level (1.98 [1.11, 3.55]; P = 0.021) were independent poor prognostic factors. The survival of the patient groups stratified by "post-NAT response criteria" which combined changes in tumor size and CA 19-9 showed significant difference (P &lt; 0.001). Such stratification was comparable to ypTNM staging in discrimination performance (difference of C-index, 0.068 [-0.012, 0.142]). Conclusions: Decrease in tumor size and CA 19-9 normalization or staying normal until the time of surgery were independent favorable factors of survival. The combination of the two factors discriminated survival comparably to ypTNM staging.[Table: see text]
The Maverick trial: A phase 2 study of abivertinib in patients (pts) with metastatic castration resistant prostate cancer (mCRPC).
Authors: Rana R. McKay, Andrew J. Armstrong, Hamid Emamekhoo, Theodore Stewart Gourdin, Elisabeth I. Heath, Arif Hussain, Moshe Chaim Ornstein, Nima Sharifi, Paul Vincent Viscuse, Ying Yan, Mike A. Royal
Journal: Journal of Clinical Oncology (2023)

TPS5106 Background: Abivertinib is a potent, small molecule third-generation tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), Bruton tyrosine kinase (BTK) receptor, and bone marrow tyrosine kinase gene on chromosome X (BMX). Abivertinib irreversibly binds to the BTK receptor, preventing the phosphorylation of the receptor, and also BMX. The adrenal-permissive HSD3B1(1245C) allele, which is present in upwards of 50% of men with prostate cancer, encodes a 3βHSD1 enzyme missense that up-regulates the rate-limiting step of androgen biosynthesis from extragonadal precursor steroids and promotes poor clinical outcomes. 3βHSD1 must be phosphorylated by BMX for androgen biosynthesis. Preclinical studies suggest BMX inhibition blocks 3βHSD1, androgen biosynthesis and CRPC in xenograft models. These provide the rationale for use of the combination of abivertinib and abiraterone to block residual androgen synthesis that escapes abiraterone inhibition. Methods: The Maverick Trial is a multicenter, open-label phase 2 study within the US Dept of Defense Prostate Cancer Clinical Trials Consortium (DOD PCCTC) of abivertinib with abiraterone in pts with mCRPC harboring the adrenal-permissive HSD3B1(1245C) allele (germline heterozygous or homozygous). HSD3B1 status will be confirmed centrally prior to enrollment via CLIA testing at the Cleveland Clinic. The study includes two cohorts: abiraterone-naïve and abiraterone-progressing. There will be cap of 50% of accrual in each cohort for pts heterozygous for the HSD3B1(1245C) allele. An interim futility analysis is embedded in each cohort, and toxicity rates will be continuously monitored for early stoppage according to predefined rules. Pts receive continuous treatment with abivertinib 200 mg BID with abiraterone 1000 mg QD + prednisone 5 mg BID until radiographic progression, unacceptable toxicity, intercurrent illness, or other reason, such as subject withdrawal. The primary endpoint is 6-month rPFS defined as percent of subjects alive and without progression by RECIST version 1.1 for measurable disease and PCWG3 criteria for bone metastases. Secondary and exploratory endpoints include objective response rate, duration of response, PSA progression, pharmacokinetics, pharmacodynamic tissue changes, and mechanisms of response and resistance to therapy via sequential tissue and blood sampling. The study is currently open at 1 site and will activate at 9 additional sites. It is sponsored by Sorrento Therapeutics, Inc, and managed by the Prostate Cancer Clinical Trials Consortium. Trial Registration: NCT05361915 Funding Source: Sorrento Therapeutics, Inc, the trial’s sponsor who is funding the trial. Clinical trial information: NCT05361915 .
Sexuality as a prognostic factor: Results of an individual participant data NOGGO-meta-analysis of 1,041 recurrent ovarian cancer patients before starting chemotherapy.
Authors: Nicole Balint, Adak Pirmorady-Sehouli, Rolf Richter, Dario Zocholl, Hannah Woopen, Klaus Pietzner, Jalid Sehouli
Journal: Journal of Clinical Oncology (2023)

e24128 Background: Until now there is very little data available about sexuality in ovarian cancer patients. Aim was analyze if sexuality is associated with clinical parameters, quality of life, prior discontinuation of chemotherapy and survival in recurrent ovarian cancer patients before starting chemotherapy. Methods: Raw data including the QLQ-C30 and QLQ-OV28 EORTC questionnaire from four phase II/III trials (“Tower”, “Treosulfan”, “Hector” and “TRIAS”) conducted by the North-Eastern German Society of Gynecological Oncology (NOGGO) were synthesized for this individual participant data meta-analysis using ANOVA and cox regression analyses. All study participants were diagnosed with recurrent ovarian cancer and data for this analysis was gained before starting chemotherapy. Three patient groups were defined: (1) patients without interest in sex and not being sexually active, (2) patients with interest in sex and not being sexually active and (3) patients with interest in sex and being sexually active. Results: Data on sexuality was available from 644 patients with 437 patients without interest in sex and not being sexually active (1), 45 patients with interest in sex and not being sexually active (2) and 162 patients with interest in sex and being sexually active (3). Women of the third group were significantly younger with a median age of 57 years at randomization compared to women of group (1) with a median age of 65 years, p &lt; 0.001. Women with interest in sex and who were sexually active showed also a significant better ECOG performance status (p &lt; 0.001), had a lower number of recurrences (p &lt; 0.001) and had less frequently ascites at diagnosis (p &lt; 0.002). There were no differences regarding FIGO stage, BMI and grading between the three groups. Sexuality was associated with global quality of life (p &lt; 0.001) and physical, psychological, social, emotional and role functionality (p &lt; 0.001). Patients who were sexually active, reported less fatigue (p &lt; 0.001), less pain (p &lt; 0.001), less sleeping disorders (p = 0.004), less diarrhea (p = 0.008), less nausea and vomiting (p = 0.007) and less loss of appetite (p &lt; 0.001). There was no association with prior discontinuation of chemotherapy. Median overall survival (OAS) was 16.7 months in platinum-resistant patients being sexually active compared to a median OAS of 8.7 months in platinum-resistant patients who are not sexually active (p = 0.016). Conclusions: Medical personnel should routinely address sexuality in ovarian cancer patients as sexuality seems to be a marker for both QoL and overall survival and warrants further investigation.
Pan-cancer diagnostic proteomic signature of tissue-of-origin (TOO) using data-independent acquisition mass spectrometry (DIA-MS) from 1289 human tissue samples.
Authors: Emma Boys, Jia (Jenny) Liu, Zhaoxiang Cai, Zainab Noor, Karen L Mackenzie, Adel Aref, Erin Sykes, Dylan Xavier, Natasha Lucas, Steven Williams, Daniel Bucio-Noble, Jennifer Koh, Peter Hains, Phillip J Robinson, Qing Zhong, Roger R Reddel
Journal: Journal of Clinical Oncology (2023)

3120 Background: Accurate tumour classification based upon tissue of origin (TOO) remains important to guide treatment selection and prognosis but can be challenging in patients with poorly differentiated malignancy, cancer of unknown primary (CUP) or those with prior malignancy. Data-independent acquisition mass spectrometry (DIA-MS)-based proteomics is emerging as a potential clinical diagnostic and prognostic tool. We aimed to develop a protein-based signature to identify histological subtype and adenocarcinoma TOO using DIA-MS data obtained from a pan-cancer study of human tissue samples as an adjunct to histopathological assessment in challenging clinical scenarios. Methods: We performed DIA-MS-based proteomic profiling of 795 fresh frozen tumour and 494 tumour-adjacent normal samples from the Victorian Cancer Biobank in a clinically orientated workflow. We filtered the cohort to include tumour types relevant to CUP. Protein quantification was derived from raw peptide intensity data. Random forest classifiers to identify histological subtype and adenocarcinoma TOO were subsequently trained and tested using 70% and 30% of the data respectively. Evaluation metrics included top-k accuracy (predicting how often the correct class is among the top k predicted classes) and area under the receiver operating curve (AUROC) (one-versus-rest) ± 95% confidence interval. Results: The final tumour cohort consisted of 427 tumour samples representing eight histological subtypes (adenocarcinoma, germ cell tumour, lymphoma, melanoma, renal cell carcinoma, sarcoma, squamous cell carcinoma, thyroid carcinoma) and seven adenocarcinoma TOO (breast, colorectal, liver, lung, ovary, pancreas, prostate). From 9,051 quantified proteins, 83 were identified with potential utility at identifying histological subtype and adenocarcinoma TOO for use in machine learning models. The histological subtype model identified cancer subtype in the test set with top-1 and top-2 accuracy of 0.95 ± 0.03 and 0.98 ± 0.02 respectively. Average test AUROC over all cancer types (n=8) was 0.98 ± 0.02. The adenocarcinoma TOO model identified tumour TOO in the test set with top-1 and top 2- accuracy of 0.88 ± 0.07 and 0.95 ± 0.04 respectively. Average test AUROC over all adenocarcinoma TOO (n=7) was 0.97 ± 0.02. Conclusions: Our clinically orientated DIA-MS-based proteomic workflow and supervised machine learning can identify protein signatures that classify histological subtype and TOO in tumour samples with high accuracy. This technology may assist diagnostic classification of cancer in challenging clinical scenarios, such as CUP.
Evolution of HER2 scores after neoadjuvant systemic therapy in breast cancer.
Authors: Esther G Chong, Won Jin Jeon, Bryan Pham, Dan Ran Castillo, Akhil Mehta, Seyed Pairawan, Laura Denham, Gayathri Nagaraj
Journal: Journal of Clinical Oncology (2023)

3139 Background: Breast cancer (BC) is a malignancy with a wide array of histopathological characteristics and tumor heterogeneity leading to major clinical implications for management. With the recent approval of antibody-drug conjugates (ADCs) for human epidermal growth factor receptor 2 (HER2)-low advanced BC, there is increased significance for characterizing the spectrum of HER2 expression in the curative setting. Methods: We conducted a single institution retrospective review of patients with BC who received neoadjuvant systemic therapy (NAST) followed by definitive surgical resection from 2008 to 2022. The initial tumor biopsies were tested for estrogen receptor (ER), progesterone receptor (PR), and HER2 status per ASCO/CAP guidelines and repeated on the residual tumor tissue after NAST. HER2 status was categorized into HER2-negative (IHC 0), HER2-low (IHC 1 or IHC 2/ Fluorescence in situ hybridization [FISH] negative), and HER2-positive (IHC 2/ FISH positive or IHC 3). Concordance and discordance with HER2 status in the pre and post NAST tumor samples were analyzed using descriptive statistics. Results: Of 340 patients with BC who received NAST, 55 patients with residual disease had pre and post treatment biomarker data available for analysis. Prevalence of HER2-low was 70.9 % (39/55) in the pretreatment tumors while it was 58.2% (32/55) in the post treatment tumors. 40% of tumors (22/55) had HER2 discordance while 60% (33/55) demonstrated concordance with HER2 expression after NAST. Among the changes in HER2 status, a shift from HER2-low to HER2-negative status occurred most frequently in 18.2% of tumors (10/55). In tumors with HER2 discordance, 36.4% (8/22) were also noted to have changes in ER or PR status while this was seen in 48.5% (16/33) of tumors with HER2 concordance. For rates of recurrence, 22.7% (5/22) of patients in the HER2 discordant group had relapsed compared to 18.2% (6/33) patients in the HER2 concordant group. Conclusions: Dynamics of HER2 expression is increasingly important in the rapidly changing therapeutic landscape of BC. Our study shows high prevalence of HER2-low expression in tumors with residual disease after NAST and frequent conversion of HER2-low to HER2-negative status with NAST. Further studies are warranted to determine the clinical and therapeutic relevance of biomarker evolution and tumor heterogeneity in the curative setting. [Table: see text]
Sociodemographic factors affecting survival in stage IIIA NSCLC treated with surgery-based treatment or definitive chemoradiation with immunotherapy consolidation: An NCDB analysis.
Authors: Janeesh Sekkath Veedu, Zhonglin Hao, Quan Chen, Bin Huang, Mridula Preetham Talari
Journal: Journal of Clinical Oncology (2023)

e18555 Background: Stage IIIA non-small cell lung cancer (NSCLC) is a heterogeneous disease treated by surgery-based approach or definitive chemoradiation (CRT) and immunotherapy (ICI) consolidation. Studies have shown that black patients in general are diagnosed at advanced stages, are less likely to receive ICI, and have lower overall survival (OS) compared to whites. Importantly, ICI was shown to impart similar or even better OS among advanced-stage black NSCLC patients, compared to whites. Geographical location and socioeconomic status have also been shown to affect outcomes. There are no studies on sociodemographic factors affecting survival in stage IIIA NSCLC in the ICI era. Methods: We used National Cancer Database (NCDB) to identify 23,110 patients with clinical stage IIIA NSCLC treated with either surgery-based approach or definitive CRT followed by ICI during 2017-2019, and surgery-based treatment or CRT during 2014-2016. We analyzed age, race, sex, insurance type, income, geographic location, Charlson Comorbidity Index (CCI) and education. Kaplan-Meier (KM) plots were used to examine survival curves and descriptive analysis was performed to examine the characteristics of sociodemographic variables by the two treatment modalities. Cox regression analysis was used to identify factors associated with OS. Results: ICI maintenance improved the OS of all stage IIIA NSCLC patients after CRT during 2017-2019 compared to CRT only in 2014-2016. On multivariate analysis of surgical and CRT-ICI cohorts, blacks had slightly better OS compared to whites (HR, 95%CI, p-value) (0.89, 0.84-0.95, &lt; 0.001) but lower than other races including Asians (0.77, 0.69-0.87, &lt; 0.001). While there was no OS difference in the surgical arm (0.94, 0.83-1.07, p = 0.356) between black and white patients, better survival was seen in blacks in the CRT-ICI arm (0.88, 0.82-0.94, &lt; 0.001). No significant interaction between race and CRT-ICI was identified which indicates the benefit of CRT-ICI is independent of the race effect. Other factors associated with lower OS were older age with age &gt; 75 HR 1.00, ages 19-39 (0.47, 0.35-0.64) ages 40-64 (0.71, 0.67-0.75), ages 65-74 (0.79, 0.76-0.83), median quartile income &lt; $40,227 (1.07, 1.01-1.14), non-metro location (1.12, 1.07-1.17), non-academic facility (1.09, 1.05-1.14), and male sex (1.24, 1.20-1.29). Insurance status had no effect on OS. Conclusions: Our study indicates that there is no survival difference between white and black patients treated with surgery, but blacks had better survival when treated with CRT-ICI. Racial disparity in NSCLC survival depends on stage and access to care. Treatment modality, income, metro location, and access to an academic center are more significant predictors of survival than race. Interestingly, health insurance had no impact on OS.
Impact of immune checkpoint inhibition on ovarian reserve in patients with melanoma enrolled in the ECOG-ACRIN E1609 adjuvant trial.
Authors: Elizabeth Iannotti Buchbinder, Zihe Song, Sandra J. Lee, Kimberly W. Keefe, Michael P. Manos, Ahmad A. Tarhini, Michael L. Dougan, Justine Vanessa Cohen
Journal: Journal of Clinical Oncology (2023)

12013 Background: Immunotherapy with immune checkpoint inhibition (ICI) is being widely adopted in the treatment of patients with a wide range of malignancies. However, we have no data on how these therapies influence fertility or ability to undergo fertility treatments after therapy. Within the melanoma community numerous women of childbearing age have been treated with ICI including ipilimumab, nivolumab and pembrolizumab. Anti-mullerian hormone (AMH) is a biomarker of ovarian reserve and a predictor of response to fertility treatments, including in vitro fertilization (IVF). In women under the age of 35 who have no reproductive pathology, AMH should be detectable and remain relatively stable over time. Above the age of 35 AMH decline accelerates as the number of eggs decreases more rapidly due to normal ovarian aging. Methods: Pre and post-treatment samples from women aged 20-35 whose melanoma was treated with 3 mg/kg ipilimumab (57%) or 10 mg/kg ipilimumab (43%) in the adjuvant setting on trial ECOG-ACRIN E1609 were analyzed in collaboration with the BWH Reproductive Endocrine Laboratory. Serum samples were tested for luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol, AMH and prolactin. Results: Samples from E1609 were available from 28 female patients with a median age of 28 (min 20, max 35). The median time between samples was 8.0 months (min 0.7, max 16.4). 53% of patients had stage IIIB melanoma, 43% stage IIIC and one patient had M1a disease. AMH, estradiol and LH significantly decreased after treatment (p &lt; 0.001, p = 0.016, p = 0.012, respectively) (Figure 1); there was no significant difference in the level of FSH and prolactin before and after the treatment (p = 0.68, p = 0.12, respectively). The median AMH was 4.24 ng/mL in the pre-treatment group and 3.51 in the post-treatment group. Conclusions: In this study of young women treated with ipilimumab there was a significant decrease in AMH before and after ICI therapy suggesting that ovarian reserve and possibly female fertility may be impacted by immune checkpoint inhibition. Further investigation is needed to look at PD-1 inhibition and combination immunotherapy effects on ovarian reserve and female fertility. In addition, there is a similar need to examine ICI effects on male fertility.